Irreversible electroporation augments -glucan induced trained innate immunity for the treatment of pancreatic ductal adenocarcinoma

BackgroundPancreatic cancer (PC) is a challenging diagnosis that is yet to benefit from the advancements in immuno-oncologic treatments. Irreversible electroporation (IRE), a non-thermal method of tumor ablation, is used in treatment of select patients with locally-advanced unresectable PC and has potentiated the effect of certain immunotherapies. Yeast-derived particulate beta-glucan induces trained innate immunity and successfully reduces murine PC tumor burden. This study tests the hypothesis that IRE may augment beta-glucan induced trained immunity in the treatment of PC. Methods beta-Glucan-trained pancreatic myeloid cells were evaluated ex vivo for trained responses and antitumor function after exposure to ablated and unablated tumor-conditioned media. beta-Glucan and IRE combination therapy was tested in an orthotopic murine PC model in wild-type and Rag(-/-) mice. Tumor immune phenotypes were assessed by flow cytometry. Effect of oral beta-glucan in the murine pancreas was evaluated and used in combination with IRE to treat PC. The peripheral blood of patients with PC taking oral beta-glucan after IRE was evaluated by mass cytometry. ResultsIRE-ablated tumor cells elicited a potent trained response ex vivo and augmented antitumor functionality. In vivo, beta-glucan in combination with IRE reduced local and distant tumor burden prolonging survival in a murine orthotopic PC model. This combination augmented immune cell infiltration to the PC tumor microenvironment and potentiated the trained response from tumor-infiltrating myeloid cells. The antitumor effect of this dual therapy occurred independent of the adaptive immune response. Further, orally administered beta-glucan was identified as an alternative route to induce trained immunity in the murine pancreas and prolonged PC survival in combination with IRE. beta-Glucan in vitro treatment also induced trained immunity in peripheral blood monocytes obtained from patients with treatment-naive PC. Finally, orally administered beta-glucan was found to significantly alter the innate cell landscape within the peripheral blood of five patients with stage III locally-advanced PC who had undergone IRE. ConclusionsThese data highlight a relevant and novel application of trained immunity within the setting of surgical ablation that may stand to benefit patients with PC.